Butterfly-shaped pigment dystrophy (BPD) was first described by Deutman and colleagues [48]. In this autosomal-dominantly inherited macular dystrophy, a spoke-like pigment pattern that may resemble the shape of a butterfly is observed in the macula [49]. Other phenotypes of the pattern dystrophy group that can be caused by PRPH2 mutations include AFVD and pseudo-Stargardt pattern dystrophy (multifocal pattern dystrophy simulating Stargardt disease/fundus flavimaculatus) [49]. BPD is genetically heterogeneous: besides mutations in the PRPH2 gene and the CTNNA1 gene, a locus on 5q21.2–q33.2 is also associated with autosomal-dominant BPD [49–54].

Patients can present with mild loss of visual acuity and/or metamorphopsia after the age of 40, but BPD patients are often asymptomatic. Patient with BPD caused by mutations in the PRPH2 gene has yellowish lesions in the macula at the level of the outer retina and retinal pigment epithelium (RPE) [49]. The lesions have three or more branches that can resemble wings of a butterfly (Fig. 2.2a). The butterfly-shaped lesions can evolve from lesions similar to adult-onset foveomacular vitelliform dystrophy. Some patients with PRPH2 mutations show a BPD lesion in the macula together with multiple flavimaculatus-like yellow flecks in the posterior pole (Fig. 2.2) [55]. These cases can be regarded as pseudo-Stargardt pattern dystrophy. On fluorescein angiography, the pigmented regions of the lesion are hypofluorescent, whereas surrounding depigmented zones and areas of chorioretinal atrophy are hyperfluorescent (see Fig. 2.2) [49, 56]. On FAF, lesions show variably increased and decreased autofluorescence (see Fig. 2.2) [57]. On optical coherence tomography, the lesions correspond to hyperreflective granular changes at the photoreceptor-RPE interface. The central visual field is normal or shows slightly decreased central sensitivity in cases without profound chorioretinal atrophy. The peripheral visual field is normal. Full-field electroretinography (ERG) is normal, except in cases that advance to extensive pseudo-Stargardt pattern dystrophy [49, 56, 58, 59]. The electro-oculogram (EOG) in BPD is normal to slightly subnormal.

Most patients with BPD have a good visual acuity in at least one eye for many decades. The development of choroidal neovascularization is very rare [60]. However, a marked decline in visual acuity can develop after the seventh decade by progressive photoreceptor and RPE atrophy in the macula [32, 61].

BPD should be differentiated from the other PRPH2-associated macular dystrophies, long-standing atrophic RPE detachments, atrophic age-related macular degeneration, and atrophic central serous chorioretinopathy. Pattern dystrophies can also be observed in association with maternally inherited diabetes and deafness (mitochondrial retinal dystrophy; see Chap. 8), myotonic dystrophy, pseudoxanthoma elasticum, and Crohn’s disease.

BPD is an autosomal-dominantly inherited macular dystrophy at the mild end of the clinical spectrum of dystrophies. However, central vision loss can still become more pronounced in the elderly population due to progressive atrophy and/or neovascularization.

The human PRPH2 gene causes a broad spectrum of retinal dystrophies, ranging from purely macular phenotypes to retinitis pigmentosa [49]. The PRPH2 protein localizes to the rim region of rod and cone outer segment discs and lamellae and plays an important role in photoreceptor outer segment morphogenesis [49]. PRPH2-associated phenotypes are inherited autosomal dominantly with the exception of digenic retinitis pigmentosa, which also requires a mutation in the ROM1 gene.

Identical PRPH2 mutations are associated with decreased penetrance and variable expression, which can result in a markedly variable spectrum of clinical pictures even in families carrying the same mutation [55]. A PRPH2-associated dystrophy that appears purely macular at first may eventually evolve into a clinical picture with widespread retinal involvement. The pseudo-Stargardt pattern dystrophy phenotype, as the name coined by Boon et al. [62] indicates, can closely mimic autosomal recessive Stargardt disease (STGD1). Up to 20 % of patients with presumed autosomal recessive Stargardt disease of the fundus flavimaculatus subtype, in whom no ABCA4 gene mutation is found, actually carry an autosomal-dominant PRPH2 mutation. This finding underscores the importance of genetic testing, as such findings greatly influence the visual prognosis, genetic counseling, and possible future therapeutic perspectives.

Most pseudo-Stargardt pattern dystrophy patients start to notice vision loss in their fifth decade, but some patients can remain asymptomatic [55]. Initial symptoms can include metamorphopsia, central vision loss, and/or scotoma. There are varying degrees of night blindness in up to half of the patients, generally with more advanced disease. On funduscopy, patients show irregular yellowish flecks in the posterior pole (Fig. 2.3), and these flecks closely resemble flavimaculatus flecks that can be seen in Stargardt disease. The flecks can gradually become confluent to form a mildly atrophic oval zone that encircles the macula and optic disc (see Fig. 2.3). The aspect of macular lesions in pseudo-Stargardt pattern dystrophy is variable: some lesions consist of a few clustered yellowish or slightly pigmented spots or have the aspect of butterfly-shaped pigment dystrophy [55]. In other cases, macular lesions can show large confluent and irregular flecks or spots.

On fluorescein angiography, the Stargardt-like flecks and the macular lesions are hyperfluorescent, sometimes with a central hypofluorescent spot (see Fig. 2.3). In contrast to most cases of Stargardt disease, there is no blockage of choroidal background fluorescence (“dark choroid”). On FAF, the Stargardt-like flecks are initially highly increased autofluorescent (see Fig. 2.3). The flecks are often bordered by small zones of decreased autofluorescence. When these flecks merge, the resulting oval zone is visible as a band of generally increased autofluorescence with granular zones of decreased autofluorescence (see Fig. 2.3) [55]. The macular lesions correspond to various patterns of increased and decreased autofluorescence. OCT shows that the Stargardt-like flecks and macular lesions correspond to abnormalities on the photoreceptor outer segment-RPE level (Fig. 2.3).

The full-field ERG is normal in early pseudo-Stargardt pattern dystrophy, when the Stargardt-like flecks are still well defined and principally located in the posterior pole. With disease progression, full-field ERG can reveal generalized cone and/or rod dysfunction [55]. In advanced cases, the photopic and scotopic full-field ERG responses become severely abnormal to non-recordable. These ERG findings indicate that pseudo-Stargardt pattern dystrophy can evolve from a dystrophy that initially appears localized to the macula—both functionally and anatomically—to widespread panretinal photoreceptor dystrophy. The EOG results vary widely but may show a subnormal to absent light rise in more than half of advanced cases [55].

In advancing disease, the retinal abnormalities extend beyond the posterior pole and do not tend to spare the peripapillary retina in contrast to Stargardt disease (see Fig. 2.3). Profound macular atrophy and marked vision loss (to as low as finger counting) generally do not develop before the age of 55. In advanced disease, patients may also show slight retinal arteriolar attenuation, perivascular and retinal hyperpigmented clumping, and temporal pallor of the optic disc [55].

In contrast to typical Stargardt disease, see Chap. 3, pseudo-Stargardt pattern dystrophy has an autosomal-dominant pattern of inheritance, a relatively late age at onset, a comparatively good visual acuity, and no dark choroid on fluorescein angiography. Other differential diagnostic entities that should be considered include autosomal-dominant Stargardt-like dystrophies such as STGD3 (caused by mutations in the ELOVL4 gene), STGD4, and pattern dystrophy associated with maternally inherited diabetes and deafness (m.3243A>G mitochondrial retinal dystrophy, see Chap. 8).

In 1950, Sjögren described a new form of retinal degenerations which he termed “dystrophia reticularis laminae pigmentosae retinae” [63]. The phenotype was later termed reticular dystrophy and was classified as one of the pattern dystrophies [2, 3]. Autosomal-dominant and autosomal recessive inheritance patterns have been described in association with this phenotype.